GUCY2C may protect Parkinson’s nerve cells: Mouse study
Protein shown as potential therapeutic target for treatment easing symptoms
GUCY2C — a protein found mainly in the gut, but also in the brain — appears to be produced in greater amounts in Parkinson’s disease as a mechanism to protect nerve cells from damage and toxic insults, a preclinical study found.
While the findings come from mice, they put forward GUCY2C as a potential therapeutic target to prevent the loss of dopaminergic neurons — the nerve cells that produce dopamine for good motor control — and ease Parkinson’s symptoms.
The study, “GUCY2C signaling limits dopaminergic neuron vulnerability to toxic insults,” was published in npj Parkinson’s disease.
There’s growing evidence that changes in the gut can affect how Parkinson’s develops and progresses. It’s believed that events such as the formation of toxic protein aggregates may start in gut cells, and then travel to the brain to cause similar events that cause disease progression.
Yet it remains unknown if targeting this gut-brain axis may be a potential strategy for treating the disease in its early stages.
Gut-brain link
GUCY2C is a protein found mainly in the cells that line the gut, where it helps to maintain a balance in water and salt. Earlier work in mice found that removing GUCY2C from the gut resulted in an increase in the activity of genes associated with Parkinson’s.
“That’s when we made that leap from the gut to the brain,” Scott A. Waldman, MD, PhD, chair of Thomas Jefferson University’s pharmacology, physiology, and cancer biology department and the study’s leader, said in a university press release. “If we removed GUCY2C in the brain, would it impact susceptibility to [Parkinson’s disease]?”
Waldman’s team first mapped out where GUCY2C was produced in mice’s brains. They found the protein in the substantia nigra pars compacta (SNpc), a region in the midbrain that is home to dopaminergic neurons and connects to the striatum, which is involved in motor control via the nigrostriatal pathway.
The researchers then engineered mice to lack the gene coding for GUCY2C. Unlike wild-type, or healthy, mice, these knock-out animals were unable to produce the protein.
It is thought that dopaminergic neurons become more prone to damage because mitochondria, the cells’ powerhouses, do not function well. Data showed that, compared with wild-type mice, animals that lacked GUCY2C had several mitochondrial abnormalities, suggesting that “loss of GUCY2C leads to mitochondrial dysfunction.”
The knock-out mice also had fewer dopaminergic neurons than wild-type mice, and their existing dopaminergic neurons in the SNpc were particularly more susceptible to damage by MPTP, a toxin that damages dopaminergic neurons via mitochondrial stress. This increased neurodegeneration was not observed in other regions of the brain.
Notably, removing the protein only from the intestine did not increase dopaminergic neuron susceptibility to damage, suggesting that GUCY2C receptors in SNpc are exerting a protective role.
Mice with normal levels of GUCY2C increased their production of the protein upon treatment with MPTP, further confirming its potential protective role. In lab-grown dopaminergic neurons, cGMP, a byproduct of GUCY2C signaling, protected against oxidative stress.
“These observations reveal a previously unexpected role for the GUCY2C-cGMP signaling axis in controlling mitochondrial dysfunction and toxicity in SNpc [dopaminergic] neurons,” the researchers wrote.
A comparison of genetic data from people with Parkinson’s with healthy individuals also showed that the gene coding for GUCY2C was significantly more active in patients’ dopaminergic neurons, similarly suggesting “a protective role for GUCY2C” in humans, the researchers wrote.
“Stimulating GUCY2C may be effective in preventing nigrostriatal neurodegeneration with limited off-target effects,” they wrote, adding that the protein may also serve as a biomarker for early-stage Parkinson’s.
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